US 7704214 B2
A volumetric flow of an analyte, including exhaled air, is fed to a gas sensor unit by used of gas flow device, which can include various sensors for the determination of nitrogen oxides. An oxidation catalyst is used when using an NO2 sensor, which converts nitrogen monoxide to nitrogen dioxide and the gas sensor unit measures the content of nitrogen dioxide. The nitrogen monoxide content is calculated from the nitrogen dioxide content. In order to eliminate cross-sensitivity moisture and ethanol are also measured. The device can be applied to the determination of nitrogen monoxide content of exhaled air.
1. Device for quantitative measurement of nitrogen monoxide in exhaled air, comprising:
a gas sensor unit including
at least one gas sensor based on a principle of work function measurement, the at least one gas sensor including a first-type gas-sensitive layer containing a porphine pigment,
an oxidation catalyst for oxidation of nitrogen monoxide to nitrogen dioxide, and
at least one further sensor for the detection of at least one of moisture and ethanol for elimination of cross-sensitivities,
wherein the device is configured to measure the nitrogen monoxide, in the exhaled air of an individual, using the gas sensor unit.
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a gas flow device for the supply of the volumetric flow of at least one of nitrogen dioxide and nitrogen dioxide and at least one component of at least one of moisture, ethanol and temperature.
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a hybrid field effect transistor including the first-type gas-sensitive layer, the first-type gas-sensitive layer being represented by a gate electrode spaced apart from a channel area used to read the work function.
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the hybrid field effect transistor includes a second-type gas-sensitive layer in the form of porous material deposited on the channel area, wherein the hybrid field effect transistor is adapted to read the work function.
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a hybrid field effect transistor including a second-type gas-sensitive layer represented by a gate electrode spaced apart from a channel area used to read the work function.
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a field effect transistor including the first-type gas-sensitive layer, the field effect transistor being adapted to read the work function and the first-type gas-sensitive layer being in the form of porous material deposited on the channel area.
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This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/DE02/01576 which has an International filing date of Apr. 30, 2002, which designated the United States of America and which claims priority on German Patent Application number DE 101 21 262.3 filed Apr. 30, 2001, the entire contents of which are hereby incorporated herein by reference.
The invention generally relates to a device and a method for the quantitative measurement of nitrogen oxides, particularly nitrogen dioxide, whereby the original content of nitrogen monoxide can be calculated. Furthermore, the invention generally relates to the application of this device in conjunction with respiratory tract diseases, such as asthma.
Among 5% of adults and 15 to 20% of children in western industrial nations asthma is one of the most frequently-occurring diseases, and this tendency is increasing.
Inflammatory conditions of the lower respiratory tracts, such as asthma or bronchiectasis, are accompanied by an increased nitrogen monoxide (NO) concentration of up to 85 ppb in the exhaled air. A reduction in the NO concentration is observed when treated with anti-inflammatory medicines such as corticosteroids. An imminent asthma attack is clearly indicated earlier by the rise in the NO content of the exhaled air than in a pulmonary function test. Nitrogen monoxide is thus a preliminary sign of an asthma attack. Measuring this NO in the exhaled air is thus an ideal method of diagnosis, particularly for deciding treatment and checking the progress of treatment of asthma and other diseases associated with inflammation of the lower respiratory tracts.
A precondition for checking the progress of treatment is, however, a mobile cost-effective measuring instrument for the quantitative detection of nitrogen dioxides regardless of location. A constant telemedical care of chronic diseases would also be of interest.
The accuracy required for the detection of nitrogen oxide in exhaled air in conjunction with the aforementioned diseases is in the area of a few ppb NO. Up to now, this could be achieved only by way of chemo luminescence measurements. The disadvantages are on one hand the size, with a weight of at least 45 kg, and on the other the high cost of such a chemo luminescence measuring apparatus. Up to now, the use of this equipment has been limited to clinics and specialized practices.
At present, peak-flow meters are used to check the progress of, for example, asthma. These are small devices that enable a simple pulmonary function test. In contrast to the complete pulmonary function test, only the highest respiration flow level, the forced expiratory value is measured. This is created at maximum exhalation. The measurement is taken several times a day. The device is relatively inexpensive. However, it measures only the end result of an asthma attack, i.e. the narrowing of the airways, and not a preliminary sign of an attack, such as for example nitrogen monoxide would indicate. Valuable time for preventive treatment is thus lost.
Further evidence of an inflammatory condition of the lower respiratory tracts can also be gained from the bronchial mucus, the sputum. A general sputum examination is macroscopic, microscopic and bacteriological and is comparatively time consuming. Obtaining mucus from children and patients with severe breathing difficulties is either impossible or very difficult.
An object of an embodiment of the invention is to provide a simple measuring system for the quantitative measurement of nitrogen oxides that is as independent of location as possible and to provide a method of operation with the nitrogen monoxide content in the exhaled air being detectable during the care of patients with respiratory illnesses.
An embodiment of the invention involves achieving a mobile cost-effective, quantitative measurement of nitrogen oxides in exhaled air by an apparatus that has a device for guiding the volumetric flow of the exhaled air in succession to an oxidation catalyst for oxidation of the nitrogen monoxide content to nitrogen dioxide, to a gas sensor unit for detection of nitrogen dioxide, moisture and ethanol and also to a unit for calculating the nitrogen monoxide values from the nitrogen dioxide values, with the moisture and ethanol concentrations eliminating the cross-sensitivity of the nitrogen oxide measurements. The combination of a very precise nitrogen oxide measuring method, with which the quantitative measurement of nitrogen oxides in the exhaled air is also possible, with a suitable test setup that guarantees the preparation of the measured gas mixture together with the calculation of the nitrogen monoxide content in the exhaled air, provides a cost-effective gas sensor system for detection of the nitrogen monoxide content and enables conclusions to be drawn regarding respiratory illnesses.
The use of a gas sensor operating on the principle of work function measurement for the detection of nitrogen oxide has energy advantages. This enables measurements to be taken with a relatively low heat energy requirement, which makes the development of a cost-effective sensor easier. It also enables applications with sensors to be opened up that because of the environment would be required to have a low electrical power. Furthermore, the use of this measuring principle has the advantages of a relatively wide range of sensitive materials that are relatively easy to prepare. Generally, however, gas sensors can be used that can detect between 3 and 100 ppb in the target area with a sufficiently high resolution. Semi-conducting metal oxide gas sensors can also particularly be used in this case, or a sensor using the principle of work function measurement.
An advantageous embodiment of the invention provides that the volumetric flow of the exhaled air is divided in the apparatus, with a part volumetric flow being directed via the oxidation catalyst and then to the nitrogen oxide measurement and another part volumetric flow being sent directly to the nitrogen oxide measurement. In this way, verification of the nitrogen monoxide in the exhaled air can particularly be determined without disturbance from nitrogen oxide from the ambient air. The actual nitrogen monoxide content of the exhaled air can be determined without error from the difference in the nitrogen dioxide concentration. The volumetric flow is measured using conventional measuring methods.
Various field effect transistors are known for nitrogen oxide detection using the principle of work function measurement, with the gas-sensitive layer being represented as a gate electrode. This gate electrode can be separated from the channel area of the field effect transistor by an air gap. A change in the potential between the gate and channel area (ΔVG) is used as the basis for a detecting measuring signal. Hybrid flip—chip arrangements of gas sensors that are designed as CMOS transistors are known, for example, from German patent applications No. 198 14 857.7 and No. 199 56 806.5. A gas sensor can also be fitted with two field effect transistors, the control characteristic of which can be matched by approximately equal air gaps between the channel area and gate electrode and the sensor layers of which can be separately read. German patent application No. 199 56 744.1 describes how the clearance between the gate electrode and channel area of a field effect transistor can be reproducibly represented by extremely precise spacers. In a different embodiment the gas-sensitive material is applied in porous form to the channel area or gate.
Cross-sensitivities can be eliminated by combining several individual sensors in a gas sensor unit in the form of various gas-sensitive layers. One layer must of course be sensitive to the target gas. Further gas-sensitive layers are designed for the detection of moisture or alcohol. A reference layer is, for example, insensitive. The integration of different gas-sensitive layers of this kind in a gas sensor unit enables the effects of moisture and alcohol to be eliminated.
To eliminate interference with the measurement due to the effect of the difference between the exhaled air temperature or measured gas temperature and sensor temperature, it is also necessary to perform temperature compensation by using a second transistor. For the selective detection of exhaled gases it is particularly necessary to take account of the effect of moisture, because the concentration of moisture can rise up to 100% relative air humidity. Furthermore, it is also recommended that the concentration of alcohol be taken into account because this component can occur in very high concentrations in the exhaled gas compared to nitrogen oxides.
A layer combination, for example, looks as follows:
target-gas sensitive layer; gas-insensitive reference layer; moisture-sensitive layer; moisture-insensitive reference layer; alcohol-sensitive layer; alcohol-insensitive layer and temperature sensor, in one unit. This enables interference with the measurement due to the influence of deviations between the temperature of the exhaled air and the sensor operating temperature, the effects of moisture and of alcohol contained in the breath to be eliminated.
Gas-sensitive layers for use in an SG-FET (Suspended Gate Field Effect Transistor) can advantageously be porphine pigments, such as phthalocyanines with a central atom of copper or lead. At sensor temperatures between 50° and 120°, nitrogen oxide sensitivities down to the lower ppb range can be verified. Detection is, as normal, aimed at nitrogen dioxide, with it being possible to calculate nitrogen monoxide using the method already described.
Other materials suitable for use in gas-sensitive field effect transistors as gas-sensitive layers for the detection of nitrogen oxide, particularly nitrogen dioxide, are fine crystalline metal oxides operated at temperatures between 80° C. and 150° C. In particular these can be SnO2, WO3, In2O3, but salts from the carbonate systems such a barium carbonate or polymers such as polysiloxane are also conceivable.
Gas-sensitive layers of polysiloxanes can also be used for the detection of ethanol. Moisture is advantageously detected using gas-sensitive layers of polyamide or polypyrrolidone.
Phthalocyanines are particularly suitable for ΔΦ measurements for detection of NO2 gases with central atoms such as copper or lead, but also the compounds with tin, nickel, cobalt or zinc as the central atom. Phthalocyanine compounds and their derivates, that have no central atom, are particularly sensitive to NO2;
instead the free binding sites in the porphine ring are saturated by hydrogen atoms, such as in the case of heliogen blue G and a phthalocyanine with phenylether side chains. At sensor temperatures between room temperature and 120° C., NO2 sensitivities down to the lower ppb range can be verified.
For verification of NO2 in the lower ppb range, porphyrines and metalloporphyrines are suitable in addition to the phthalocyanine pigments. These include the metal-free porphyrines such as protoporphyrine IX sodium salt or metal-containing porphyrines such as cobalt protoporphyrines IX. To improve the response times of the sensors, the sensor layers are used at temperatures from room temperature up to 75° C.
An advantage of these investigated materials is that, compared with the phthalocyanines, at relatively low temperatures they have very small response times and a high NO2 sensitivity. Thus, the sensors can also be operated at lower heater voltage, thus significantly reducing the power requirements of the sensor.
The present invention will become more fully understood from the detailed description of preferred embodiments given hereinbelow and the accompanying drawings, which are given by way of illustration only and thus are not limitative of the present invention, and wherein:
To determine the nitrogen oxide in exhaled air for the detection of asthma, it must be guaranteed that only the exhaled bronchial air is detected. Because air exhaled through the nose has a nitrogen oxide concentration increased by a factor of 1000, the volume of exhaled air to be measured must be precisely defined. This can be achieved by exhaling against a resistance, for example through a valve that opens only at increased air pressure, so that the soft pallet automatically closes and the breath is exhaled only through the mouth and not through the nose.
To verify nitrogen monoxide in the exhaled air it is necessary to preclude interference due to nitrogen oxide from the ambient air. To do this, the volumetric flow of the exhaled air is divided. One part of the exhaled air containing nitrogen is used directly for determining the residual concentration of NO2. The second part is oxidized to nitrogen dioxide by way of a converter (oxidation catalyzer) and the nitrogen dioxide concentration is then measured. The actual nitrogen monoxide content of the exhaled air can be precisely determined from the difference between the concentrations of nitrogen dioxide.
The main advantages of the overall system are that a non-invasive method of measurement is used. The measurements are repeatable a large number of times and can thus also be used particularly to monitor the progress of therapy, to diagnose asthma in children, for the early detection of asthma or for preventive medicinal measures. The system with a gas sensor unit presented here is an exhaled gas sensor that is smaller to manufacture and more cost-effect to use and is therefore also suitable for use outside clinics and doctors' practices.
Because of the occurrence of nitrous oxides in the ambient air in concentration ranges relevant to the verification of an asthma illness, the disturbance effects from the ambient air must be eliminated. To do this, the nitrogen dioxide concentration already present in the exhaled air or that may enter the exhaled air due to sampling errors, must be directly determined by means of nitrogen dioxide gas sensors. In parallel with this, the nitrogen monoxide content in the exhaled air is quantitatively converted to nitrogen dioxide by means of a converter and quantified by a second nitrogen dioxide sensor. The differential signal of these two measurements then provides the amount of nitrogen monoxide in the exhaled air and verification for the assessment of the asthma illness. The described method is schematically shown in
The elimination of the cross-sensitivities is accompanied by an improvement in the measuring accuracy. The sensor system for verification of an asthma illness is fitted with at least three sensors. The target gas nitrogen oxide, the humidity and ethanol are detected. An analytical circuit and the transmission of the data in a telemedical network result in particular advantages with regard to the detection and treatment of asthma.
The determination of the concentration of moisture and the direct signal correction with the NO sensor signal is necessary to eliminate the cross-sensitivity of the NO sensor layer to moisture. The determination of the alcohol concentration in the exhaled air is necessary to assess the quality of the NO measurement, because alcohol in the exhaled air can occur up to a level of 1500 ppm and can lead to falsification of the NO detection in the lower ppb range.
A linking of the output signals of the system described by an embodiment of the invention enables asthma monitoring, with the nitrogen monoxide detection in the exhaled air being used as an essential part. The associated advantages are a simple location-independent operation and the ability to carry out regular reproducible measurements. The continual progress data obtained in this way provides information on factors that trigger an attack or on systematic incorrect behavior by patients. Because a change in the condition of the illness is signaled early in the NO values of the exhaled air, communicating the data quickly to the doctor providing the treatment enables medication to be adapted in good time, thus leading to a minimization of the amount of medication.
The advantages of the embodiments of the invention are revealed in particular in the application.
The determination of NO in exhaled gases is a non-invasive method of measurement that is particularly suitable for repeated applications, such as monitoring the progress of therapy, the diagnosis of asthma in children, the early detection of asthma or for preventive medical measures.
False measurements due to changes in temperatures at sensors or the presence of moisture can be corrected.
Interference due to high concentration of ethanol can be detected and corrected. The gas sensor system can be used for any number of repeatable measurements of the exhaled air.
The presented gas sensor is used for the manufacture of smaller and more cost-effective respiratory gas sensors and is therefore also suitable for use outside clinics and doctors' practices.
Construction of a measuring system for determining NO in exhaled air: The measuring system includes a sampling system and a gas sensor system. The sampling system, as shown in
With aid of the sampling system, zero air, i.e. air that is free of NO and NO2, is inhaled before the measurement by way of an NO/NO2 scrubber. The NO/NO2 scrubber includes a filter combination of active carbon and aluminum oxide or zeolite, or silica gel or a combination of these materials. This NO/NO2 scrubber is fitted with a one-way valve so that inhalation is possible only through the NO/NO2 scrubber and not through the converter column. This arrangement prevents NO or NO2 gas, present in the ambient air in substantially higher concentrations than in the lungs, being inhaled into the lungs and thus increasing the levels in the exhaled air.
The exhaled air is blown through a second one-way valve to the NO/NO2 converter and not through the NO/NO2 scrubber. The converter includes potassium permanganate immobilized on silica gel.
The purpose of the converter is to:
convert the NO gas to NO2 gas at room temperature and
reduce the moisture in the exhaled gas.
Advantages of embodiments of the invention lie particularly in the application:
Air free of NO and NO2 is inhaled, which indicates that the measurement is free of interference due to ambient air.
Dew formation on the sensor is avoided because silica gel absorbs part of the moisture in the breath.
There is no heater for the converter because oxidation of NO gas to NO2 gas takes place at room temperature.
The replacement of system parts to be renewed, such as a mouthpiece that has to be renewed for reasons of hygiene or a converter that becomes used up and has to be replaced, is flexible and fast.
The gas sensor measuring system corresponding to
The gas sensor system is also fitted with an analytical circuit to read the signals from the gas sensors and reference sensors, perform moisture correction, calculate the gas concentration and determine the NO concentration. The NO content is displayed on a digital display on the measuring system and is available for telemedical data transmission.
Exemplary embodiments being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the present invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.